Patent DE-19929065-A1 (DE)
Title: Synergistic drug combination, especially for treating cardiovascular diseases associated with metabolic disorders, comprising bi- or tricyclic aza-heterocyclic MTP inhibitor and HMG-CoA reductase inhibitor
Inventor: GRUETZMANN RUDI
IPC: A61P3/10
Filed: 1999-06-25
Abstract: A combination of MTP inhibitor(s) (A), selected from 5 classes of specific bi- or tricyclic aza-heterocyclic compounds, and HMG-CoA reductase inhibitors (B) is used in the treatment or prophylaxis of cardiovascular diseases.  The use of a combination of at least one MTP inhibitor (A) and at least one HMG-CoA reductase inhibitor (B) is claimed in the treatment or prophylaxis of diseases. (A) is selected from tricyclic pyrrole derivatives of formula (A1), heterocyclic-substituted phenylacetamide derivatives of formula (A2) or (A3), purine derivatives of formula (A4) and indolo-pyrimidine derivatives of formula (A5) (including isomers and salts).  R1a + R2a = group completing a phenyl or pyridyl ring or a dihydropyridone ring of formula (a) (all rings being optionally substituted by 1-3 of halo, CF3, COOH, OH, alkoxy, alkoxycarbonyl or alkyl (itself optionally substituted by OH or 1-4C alkoxy));  R3a + R4a  = group completing a pyridyl ring or a 4-8 membered cycloalkene or oxocycloalkene residue (all rings being optionally substituted as in R1a/R2a);  Da  = H, 4-12C cycloalkyl or 1-12C alkyl;  Ea  = CO or CS; La  = O, S or N(R9a);  R9a  = H or alkyl (optionally substituted by OH or Ph);  R5a  = Ph or 5-7 membered (un)saturated heterocycle (both optionally substituted by 1-3 of NO2, COOH, halo, CN, alkenyl, alkoxycarbonyl and alkyl (itself optionally substituted by OH, COOH, alkoxy or alkoxycarbonyl) and/or by OR10a or NR11aR12a);  R10a  = H, alkyl or alkenyl;  R11a, R12a  = Ph, H, alkyl or up to 8C acyl (optionally substituted by NR13aR14a);  R13a, R14a  = H or up to 8C acyl;  R6a  = H, COOH, (1-5C) alkoxycarbonyl or alkyl (optionally substituted by OH or OCOR15a);  R15a  = Ph (optionally substituted by 1-3 of halo, OH or 1-5C alkyl); or 1-22C alkyl or 2-22C alkenyl (both optionally substituted by OR16a);  R16a  = H, CH2Ph, CPh3 or alkyl; R7a  = H;  or R6a + R7a  = =O;  Ab  = one of 9 specified bicyclic heterocyclic groups;  Db, Eb  = H, halo, CF3, OH, COOH, alkoxy, alkoxy or alkoxycarbonyl;  Zb  = O or S;  R1b  = 3-10C cycloalkyl, 1-10C alkyl or phenyl (optionally substituted by 1 or 2 of halo, NO2, CN, OH, 1-4C alkyl and 1-4C alkoxy);  R2b  = H or 1-3C alkyl;  R3b  = H, 1-5C alkyl, 3-7C cycloalkyl, phenyl or 5-7 membered aromatic heterocyclyl (optionally substituted by 1-3 of halo, NO2, Ph, OH, alkyl and alkoxy);  R4b  = H, CH2OH or CH2OCOR11b;  R11b  = H, 1-8C alkyl or phenyl (optionally substituted by 1-3 of halo, OH, CN, 1-4C alkyl and 1-4C alkoxy);  Dc  = imidazolyl, aza-imidazolyl or indolyl group of formula (k) or (l);  Tc  = N or CH;  R6c-R11c  = H, CF3, halo, alkyl or alkoxy;  R5c, R8c, R9c  = H, 3-6C cycloalkyl, Ph, alkoxycarbonyl or alkyl (optionally substituted by halo); or R5c may also be benzyl if Tc = N;  Ec, Lc  = H, halo, CF3, OH, COOH, alkyl, alkoxy or alkoxycarbonyl;  R1c-R4c  = as R1b-R4b respectively;  Ad  = one of 2 specified purinyl residues;  Dd, Ed  = H, halo, CF3, OH, COOH, alkyl, alkoxy or alkoxycarbonyl;  R1d  = H or cycloalkyl; 1-8C alkyl or 2-8C alkenyl (both optionally substituted by 3-6C cycloalkyl, Ph or 5- or 6-membered aromatic heterocyclyl); or Ph or 5- or 6-membered aromatic heterocyclyl (where the ring systems are optionally substituted by 1-3 of halo, Ph, CF3, 1-5C alkyl, 1-5C alkoxy, OH or NR9dR10d);  R9d, R10d  = H, Ph, 1-5C alkyl or 1-5C acyl; Ld  = O or S;  R2d  = SH, OH, 1-8C alkoxy or -N(R13d)-CHR14dR15d;  R13d  = H or 1-4C alkyl;  R14d  = H, Ph or 5- or 6-membered aromatic heterocyclyl;  R15d  = H or 1-8C alkyl (optionally substituted by OH);  Ae, De, Ee, Ge, Le, Me  = H, halo, CF3, COOH, OH, alkoxy, alkoxycarbonyl or alkyl (optionally substituted by OH or 1-4C alkoxy);  R1e, R2e  = H, cycloalkyl, 1-10C alkyl (optionally substituted by 3-6C cycloalkyl) or Ph (optionally substituted by halo or CF3);  or CR1eR2e  = 4-8C cycloalkylidene; R3e  = phenyl (optionally substituted by 1-3 of NO2, COOH, halo, CN, alkenyl, alkoxycarbonyl or alkyl (optionally substituted by OH, COOH, 1-4C alkoxy or (1-4C) alkoxycarbonyl and/or by OR4e or NR5eR6e);  R4e = H, alkyl or alkenyl;  R5e, R6e  = Ph, H, alkyl or up to 8C acyl (optionally substituted by NR7eR8e);  R7e, R8e  = H or up to 8C acyl; unless specified otherwise alkyl moieties have 1-6C, alkenyl moieties 2-6C and cycloalkyl moieties 3-8C; heterocycles contain 1-3 of S, N and/or O as heteroatom(s).  The full definitions are given in the DEFINITION (Full Definitions) field.  Independent claims are included for:  (1) medicaments containing a combination of (A), (B) and optionally one or more further components; and  (2) production of the medicaments by converting (A), (B) and optionally further components into a suitable application form with auxiliaries and carriers.